Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/48—Separation; Purification; Stabilisation; Use of additives
  • C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D9/00—Crystallisation
  • B01D9/0018—Evaporation of components of the mixture to be separated
  • B01D9/0022—Evaporation of components of the mixture to be separated by reducing pressure
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D9/00—Crystallisation
  • B01D9/02—Crystallisation from solutions
  • B01D9/04—Crystallisation from solutions concentrating solutions by removing frozen solvent therefrom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C35/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic
  • C07C35/08—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings
  • C07C35/14—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings with more than one hydroxy group bound to the ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
  • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
  • C07C39/10—Polyhydroxy benzenes; Alkylated derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/48—Separation; Purification; Stabilisation; Use of additives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/48—Separation; Purification; Stabilisation; Use of additives
  • C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D11/00—Solvent extraction
  • B01D11/02—Solvent extraction of solids
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D9/00—Crystallisation
  • B01D2009/0086—Processes or apparatus therefor

Definitions

• the invention relates to a method for preparing medicinal chlorogenic acid.
• Chlorogenic acid has a wide range of antibacterial effects, but can be inactivated by proteins in the body. Similar to caffeic acid, oral excitability can be increased in rats when administered orally or intraperitoneally. It can increase the intestinal peristalsis of rats and mice and the tension of rat uterus. It has a beneficial effect on bile secretion in rats. It has a sensitizing effect on humans, and after inhaling plant dust containing this product, asthma, dermatitis, etc. may occur.
• CN201010558366 discloses a method for producing chlorogenic acid crystal, belonging to natural product extraction.
• a 50% methanol chlorogenic acid solution is crystallized at 0 ° C, the crystals are filtered, and the crystallization mother liquid is frozen and frozen at -50 ° C, and then the ice is taken out and broken into powders by a ice machine.
• the ice powder is sent to a centrifugal separator for centrifugation to obtain a high concentration methanol chlorogenic acid solution. Water was then added to the solution to a methanol concentration of 50% methanol chlorogenic acid solution. The solution was crystallized at 0 ° C, and the crystals were separated and lyophilized in vacuo to obtain chlorogenic acid in an amount of 98% or more.
• invention name a method for preparing chlorogenic acid products from Eucommia ulmoides leaves
• the invention relates to a method for preparing chlorogenic acid products from Eucommia ulmoides leaves, which is extracted by deionized water at room temperature, pressed (or centrifuged), large The process of enrichment by pore adsorption column chromatography, ethyl acetate extraction, and deionized water recrystallization.
• chlorogenic acid purification methods include resin column chromatography, polyamide column chromatography, gel chromatography, high performance liquid chromatography, crystallization and recrystallization.
• Resin column chromatography which can enrich and purify chlorogenic acid, but the purity and impurities of the sample cannot meet the requirements of medicinal requirements only by this method; polyamide column chromatography, which can obtain chlorogenic acid and flavonoids.
• the technical solution of the present invention provides a preparation method of chlorogenic acid.
• the invention provides a preparation method of medicinal chlorogenic acid, which comprises the following steps:
• the sample is prepared into a solution containing chlorogenic acid 20mg/ml-2000mg/ml with purified water, and filtered; the sample is extracted from Eucommia ulmoides leaves to extract the extract with chlorogenic acid content of not less than 60%.
• the preparation temperature is not higher than 60 ° C;
• thawing filtration the frozen ice cubes are thawed at 5-60 ° C, and the temperature of the thawing solution is kept no higher than 5 ° C, and filtered;
• organic residue treatment of the residue the filter residue obtained by filtration is fully dissolved and filtered with an organic solvent; wherein the organic solvent is one of methyl acetate, ethyl acetate, propyl acetate and butyl acetate; the dissolution temperature is not higher than 60 °C;
• f according to the difference in the content of chlorogenic acid in the sample, select the ae step repetition number; when the extract content is 60-80%, the ae step is repeated twice; when the extract content is 80-90%, Repeat the operation of the ae step; when the extract content is above 90%, no repeated operation is required;
• Drying After filtering the crystal body, drying is carried out under low temperature conditions; the drying temperature is not higher than 60 ° C, and it can be dried under normal pressure or under negative pressure.
• Sample aqueous phase treatment The sample is prepared into a solution containing chlorogenic acid of 500 mg/ml with purified water, and filtered; wherein the sample is extracted from the leaves of Eucommia ulmoides leaves to extract an extract having a chlorogenic acid content of 90%; the preparation temperature is 40 °C;
• thawing filtration the frozen ice cubes are thawed at 25 ° C, and the temperature of the thawing solution is kept not higher than 5 ° C, and filtered;
• organic residue treatment of the residue the filter residue obtained by filtration is fully dissolved with an organic solvent and filtered;
• the organic solvent is ethyl acetate; the dissolution temperature is 60 ° C;
• the invention also provides chlorogenic acid prepared by the method.
• the chlorogenic acid content is more than 98%, containing one to six related substances, including 5-caffeoyl quinic acid, 4-vinyl catechol, caffeic acid, 4-caffeoyl quinic acid, 3-
• the content of coumaric quinic acid and chlorogenic acid methyl ester is less than 0.5%.
• the invention adopts a method combining water and an organic solvent, utilizes the difference of solubility of chlorogenic acid and water-soluble impurities in water at different temperatures, removes water-soluble impurities in the extract by means of freezing and re-dissolving in an aqueous phase; and reuses chlorogenic acid
• the difference in solubility between the fat-soluble impurities in the organic solvent and the fat-soluble impurities in the extract are obtained by concentrating and crystallizing the organic solution.
• the separation and purification of the chlorogenic acid extract by the two different polar solvents can well remove the water-soluble impurities and the fat-soluble impurities in the extract, so that the impurity content of the final product meets the medicinal requirements; Simple, organic solvent can be recycled, low cost, suitable for further separation and purification of chlorogenic acid extract extracted by various methods, especially suitable for the preparation of medicinal chlorogenic acid.
• Sample aqueous phase treatment the sample is prepared into a solution containing chlorogenic acid 500 mg/ml with purified water, and filtered; wherein the sample is extracted from Eucommia ulmoides leaves to extract an extract having a chlorogenic acid content of 90%; the preparation temperature is 40 °C.
• the organic residue treatment of the residue the filter residue obtained by filtration, fully dissolved with an organic solvent, and filtered; wherein the organic solvent is ethyl acetate; the dissolution temperature is 60 ° C;
• Sample aqueous phase treatment The sample is prepared into a solution containing chlorogenic acid of 800 mg/ml with purified water. Filtration; wherein the sample is extracted from the leaves of Eucommia ulmoides leaves to extract an extract having a chlorogenic acid content of 60%; the preparation temperature is 50 ° C;
• the organic residue treatment of the residue the filter residue obtained by filtration, fully dissolved and filtered with an organic solvent; wherein the organic solvent is propyl acetate; the dissolution temperature is 60 ° C;
• Sample aqueous phase treatment The sample is prepared into a solution containing chlorogenic acid 20 mg/ml with purified water and filtered; the sample is extracted from Eucommia ulmoides leaves to extract an extract having a chlorogenic acid content of 85%; the preparation temperature is 20 °C;
• the organic residue treatment of the residue the filter residue obtained by filtration, fully dissolved and filtered with an organic solvent; wherein the organic solvent is methyl acetate; the dissolution temperature is 20 ° C;
• Sample aqueous phase treatment The sample is prepared into a solution containing chlorogenic acid 100 mg/ml with purified water, and filtered; wherein the sample is extracted from the Eucommia ulmoides leaves to extract an extract having a chlorogenic acid content of 72%; the preparation temperature is 30 °C;
• the organic residue treatment of the residue the filter residue obtained by filtration, fully dissolved and filtered with an organic solvent; wherein the organic solvent is butyl acetate; the dissolution temperature is 60 ° C;
• Drying After filtering the crystals, drying is carried out under low temperature conditions; the drying temperature is 60 ° C, and drying is carried out under a vacuum condition.
• Sample aqueous phase treatment The sample was prepared into a solution containing chlorogenic acid 2000 mg/ml with purified water and filtered; the sample was extracted from Eucommia ulmoides leaves to extract an extract having a chlorogenic acid content of 68%; the preparation temperature was 60. °C;
• the organic residue treatment of the residue the filter residue obtained by filtration, fully dissolved and filtered with an organic solvent; wherein the organic solvent is ethyl acetate; the dissolution temperature is 50 ° C;
• Sample aqueous phase treatment The sample is prepared into a solution containing chlorogenic acid of 1500 mg/ml with purified water, and filtered; wherein the sample is extracted from Eucommia ulmoides leaves to extract an extract having a chlorogenic acid content of 95%; the preparation temperature is 60 °C;
• the organic residue treatment of the residue the filter residue obtained by filtration, fully dissolved and filtered with an organic solvent; wherein the organic solvent is propyl acetate; the dissolution temperature is 60 ° C;
• Example 7 The quality of the medicinal chlorogenic acid of Example 1-6 of the present invention
• the method of detecting the content is:
• Determination method Take the appropriate amount of this product, accurately weighed, add mobile phase to make about 10 ⁇ g solution per 1ml, as the test solution, accurately measure 20 ⁇ l into the liquid chromatograph, record the chromatogram; take chlorogenic acid control Appropriate amount, precision weighing, add mobile phase to make 10 ⁇ g solution per 1ml, the same method; according to the external standard method to calculate the peak area, that is;
• the detection method of impurities is:
• the peak retention time is 3 times; if there is a caffeic acid impurity peak in the chromatogram of the test solution, it is calculated according to the external standard method; if there are other impurity peaks, it is calculated according to the self-control method.

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• Organic Chemistry (AREA)
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• 2014
  • 2014-11-26 JP JP2017523845A patent/JP6488379B2/ja active Active
  • 2014-11-26 WO PCT/CN2014/092262 patent/WO2016082122A1/zh active Application Filing
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